CN103275034A - Preparation method of micromolecule cathepsin D inhibitor - Google Patents
Preparation method of micromolecule cathepsin D inhibitor Download PDFInfo
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- CN103275034A CN103275034A CN2013101306700A CN201310130670A CN103275034A CN 103275034 A CN103275034 A CN 103275034A CN 2013101306700 A CN2013101306700 A CN 2013101306700A CN 201310130670 A CN201310130670 A CN 201310130670A CN 103275034 A CN103275034 A CN 103275034A
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Abstract
The invention discloses a preparation method of a micromolecule cathepsin D inhibitor. The preparation method comprises the following steps that 2-mercaptobenzothiazole or its derivatives and 4-iodoaniline as starting materials undergo a reaction in a water phase by catalytic C-S coupling to produce 4-(2-benzothiazolylthio)aniline or its corresponding derivatives (A); and the 4-(2-benzothiazolylthio)aniline or its corresponding derivatives (A), and 3,5-dichloro-2-hydroxybenzoic acid undergo an amidation reaction to produce the micromolecule cathepsin D inhibitor (B). The preparation method has the advantages of easily available raw materials, simple reaction conditions, simple and convenient operation, low toxicity and pollution, simple post-treatment processes, high yield and high purity.
Description
Technical field
The invention belongs to the pharmaceutical chemistry synthesis technical field, relate in particular to the preparation method of small molecule cathepsin D inhibitor.
Background technology
Cathepsin D is a kind of lysosome aspartate protease, studies show that itself and senile dementia, mammary cancer and uterus carcinoma have substantial connection.Stephen Wong research group is by high flux screening optimization, obtained the compound that a class has very strong inhibition cathepsin D effect, its mother nucleus structure is a N-[4-(benzothiazole-2-sulfo-) aryl]-3,5-two chloro-2-hydroxybenzamides, concrete molecular structural formula is as follows:
Preparation patent protection to this compounds is not arranged at present as yet; mainly be to prepare 2-(4-nitrophenylsulfenyl) benzothiazole by 2-mercaptobenzothiazole and parachloronitrobenzene earlier now in the bibliographical information, in noxious solvent DMF, finish aftertreatment inconvenience; environmental pollution is serious; it is amino that the nitro that then reduces becomes, and prepares this compounds with 3,5-, two chloro-2-hydroxybenzoyl chlorides again; reaction yield is low; 39% productive rate is only arranged, and long reaction time reaches 6 days.
Summary of the invention
The objective of the invention is to overcome among the preparation method of existing this micromolecular cathepsin D inhibitor that productive rate is low, long reaction time, technical problem such as seriously polluted, a kind of preparation method of small molecule cathepsin D inhibitor of easy environmental protection is provided.
Purpose of the present invention is achieved through the following technical solutions:
The preparation method of small molecule cathepsin D inhibitor, its concrete steps are:
(Ι) preparation of 4-(2-[4-morpholinodithio sulfenyl) aniline and derivative thereof
In reactor, add earlier 2-mercaptobenzothiazole or its derivative successively, to amino iodobenzene, catalyzer, alkali and solvent, heating reflux reaction, reaction solution are through extraction, drying is crossed post and is got 4-(2-[4-morpholinodithio sulfenyl) aniline and corresponding derivative thereof.
(Π) preparation of small molecules cathepsin D inhibitor
With gained 4-(2-[4-morpholinodithio sulfenyl) aniline in the step (Ι) or its derivative and 3; 5-two chloro-2 hydroxybenzoic acids are dissolved in the organic solvent, add acylating agent, reflux; reaction finishes, and aftertreatment is crossed post and got required small molecules cathepsin D inhibitor.
2-mercaptobenzothiazole derivative in the preferred steps (Ι) is 2-sulfydryl-6-chloro benzothiazole, 2-sulfydryl-6-methoxyl group benzo thiazole, 2-sulfydryl-5-trifluoromethoxy benzo thiazole, 2-sulfydryl-5-methoxyl group benzo thiazole or 2-sulfydryl-5-ethoxyl benzo thiazole; Described catalyzer is CuI, Cu
2O, CuBr, CuCl, CuO, CuCl
2.2H
2O, CuSO
4.5H2
OOr Cu; Described alkali is K
2CO
3, K
3PO
4, Na
2CO
3, KOH, NaOH or KOtBu; Acylating agent described in the step (Π) is a kind of in 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride (EDC) or the dicyclohexylcarbodiimide (DCC).
Solvent described in the preferred steps (Ι) is water; Organic solvent described in the step (Π) is methylene dichloride.Wherein the add-on of solvent and organic solvent gets final product for the solubilizing reaction thing.
Temperature of reaction described in the preferred steps (Ι) is 100-140 ℃, and the reaction times is 4-36h; Temperature of reaction described in the step (Π) is 20-40 ℃, and the reaction times is 4-48h.
The mol ratio of the catalyzer described in the preferred steps (Ι) and 2-mercaptobenzothiazole or its derivative is 0.01-0.3:1, is 1-3:1 to the mol ratio of amino iodobenzene and 2-mercaptobenzothiazole or its derivative; The mol ratio of alkali and 2-mercaptobenzothiazole or its derivative is 1-5:1; The mol ratio of the acylating agent described in the step (Π) and 3,5-, two chloro-2 hydroxybenzoic acids is 1-2:1, and the mol ratio of 4-(2-[4-morpholinodithio sulfenyl) aniline and corresponding derivative thereof and 3,5-, two chloro-2 hydroxybenzoic acids is 1-2:1.
Beneficial effect:
Raw material required for the present invention is cheap and easy to get, and reaction conditions is simple, and is easy and simple to handle, and toxicity and pollution are little, and aftertreatment is simple, yield and purity height.
Description of drawings
Fig. 1 is a kind of small molecules cathepsin D inhibitor N-[4-(benzothiazole-2-sulfo-) aryl prepared among the embodiment 1]-3, the nuclear magnetic spectrum of 5-two chloro-2-hydroxybenzamides.
Embodiment
Embodiment 1:
(Ι) preparation of 4-(2-[4-morpholinodithio sulfenyl) aniline
In reactor, add successively earlier 2-mercaptobenzothiazole (1.67g, 10mmol), to amino iodobenzene (2.63g, 12mmol), Catalysts Cu I(0.19g, 1mmol), Na
2CO
3(1.06g, 10mmol) and H
2O(20mL), be heated to 120 ℃ of back flow reaction 24h, reaction finishes, be cooled to room temperature, the reaction solution ethyl acetate extraction, the gained organic phase is through saturated aqueous common salt washing, anhydrous sodium sulfate drying, be spin-dried for, PE:EA=6:1 crosses post and gets 4-(2-[4-morpholinodithio sulfenyl) aniline 2.09g, yield 86.0%.
(Π) a kind of preparation of small molecules cathepsin D inhibitor
(1.29g, 5mmol) with 3, (1.04g 5mmol) is dissolved in CH to 5-two chloro-2 hydroxybenzoic acids with gained 4-among the step Ι (2-[4-morpholinodithio sulfenyl) aniline
2CL
2(20mL), add acylating agent 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride (EDC) (0.96g, 5mmol), be heated to 40 ℃ of back flow reaction 8h, reaction finishes, and revolves desolventizing, and PE:EA=3:1 crosses post and gets required small molecules cathepsin D inhibitor N-[4-(benzothiazole-2-sulfo-) aryl]-3,5-two chloro-2-hydroxybenzamide 1.79g, yield 80.7%; Prepared a kind of small molecules cathepsin D inhibitor N-[4-(benzothiazole-2-sulfo-) aryl]-3, the nuclear magnetic spectrum of 5-two chloro-2-hydroxybenzamides is as shown in Figure 1.
Embodiment 2:
(Ι) preparation of 4-(2-(6-chloro benzothiazole sulfenyl)) aniline
In reactor, add successively earlier 2-sulfydryl-6-chloro benzothiazole (2.02g, 10mmol), to amino iodobenzene (2.63g, 12mmol), Catalysts Cu I(0.19g, 1mmol), Na
2CO
3(1.06g, 10mmol) and H
2O(20mL), be heated to 120 ℃ of back flow reaction 24h, reaction finishes, be cooled to room temperature, the reaction solution ethyl acetate extraction, the gained organic phase is spin-dried for through saturated aqueous common salt washing, anhydrous sodium sulfate drying, PE:EA=6:1 crosses post and gets 4-(2-(6-chloro benzothiazole sulfenyl)) aniline 2.46g, yield 84.0%.
(Π) a kind of preparation of small molecules cathepsin D inhibitor
(1.46g, 5mmol) with 3, (1.04g 5mmol) is dissolved in CH to 5-two chloro-2 hydroxybenzoic acids with gained 4-among the step Ι (2-(6-chloro benzothiazole sulfenyl)) aniline
2CL
2(20mL); add acylating agent 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride (EDC) (0.96g; 5mmol); be heated to 40 ℃ of back flow reaction 8h; reaction finishes, and revolves desolventizing, and PE:EA=3:1 crosses post and gets required small molecules cathepsin D inhibitor N-[4-(6-chloro benzothiazole-2-sulfo-) aryl]-3; 5-two chloro-2-hydroxybenzamide 1.87g, yield 78.0%.
Embodiment 3:
(Ι) preparation of 4-(2-(6-methoxyl group benzo thiazole sulfenyl)) aniline
In reactor, add successively earlier 2-sulfydryl-6-methoxyl group benzo thiazole (1.97g, 10mmol), to amino iodobenzene (2.63g, 12mmol), Catalysts Cu I(0.19g, 1mmol), Na
2CO
3(1.06g, 10mmol) and H
2O(20mL), be heated to 120 ℃ of back flow reaction 24h, reaction finishes, be cooled to room temperature, the reaction solution ethyl acetate extraction, the gained organic phase is spin-dried for through saturated aqueous common salt washing, anhydrous sodium sulfate drying, PE:EA=6:1 crosses post and gets 4-(2-(6-methoxyl group benzo thiazole sulfenyl)) aniline 2.39g, yield 83.2%.
(Π) a kind of preparation of small molecules cathepsin D inhibitor
(1.44g, 5mmol) with 3, (1.04g 5mmol) is dissolved in CH to 5-two chloro-2 hydroxybenzoic acids with gained 4-among the step Ι (2-(6-methoxyl group benzo thiazole sulfenyl)) aniline
2CL
2(20mL); add acylating agent 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride (EDC) (0.96g; 5mmol); be heated to 40 ℃ of back flow reaction 8h; reaction finishes, and revolves desolventizing, and PE:EA=3:1 crosses post and gets required small molecules cathepsin D inhibitor N-[4-(6-methoxyl group benzo thiazole-2-sulfo-) aryl]-3; 5-two chloro-2-hydroxybenzamide 1.86g, yield 78.3%.
Embodiment 4:
(Ι) preparation of 4-(2-(5-trifluoromethoxy benzo thiazole sulfenyl)) aniline
In reactor, add successively earlier 2-sulfydryl-5-trifluoromethoxy benzo thiazole (2.51g, 10mmol), to amino iodobenzene (2.63g, 12mmol), Catalysts Cu I(0.19g, 1mmol), Na
2CO
3(1.06g, 10mmol) and H
2O(20mL), be heated to 120 ℃ of back flow reaction 24h, reaction finishes, be cooled to room temperature, the reaction solution ethyl acetate extraction, the gained organic phase is spin-dried for through saturated aqueous common salt washing, anhydrous sodium sulfate drying, PE:EA=6:1 crosses post and gets 4-(2-(5-trifluoromethoxy benzo thiazole sulfenyl)) aniline 2.89g, yield 84.5%.
(Π) a kind of preparation of small molecules cathepsin D inhibitor
(1.71g, 5mmol) with 3, (1.035g 5mmol) is dissolved in CH to 5-two chloro-2 hydroxybenzoic acids with gained 4-among the step Ι (2-(5-trifluoromethoxy benzo thiazole sulfenyl)) aniline
2CL
2(20mL); add acylating agent 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride (EDC) (0.96g; 5mmol); be heated to 40 ℃ of back flow reaction 8h; reaction finishes, and revolves desolventizing, and PE:EA=3:1 crosses post and gets required small molecules cathepsin D inhibitor N-[4-(5-trifluoromethoxy benzo thiazole-2-sulfo-) aryl]-3; 5-two chloro-2-hydroxybenzamide 2.08g, yield 78.6%.
Embodiment 5:
(Ι) preparation of 4-(2-[4-morpholinodithio sulfenyl) aniline
In reactor, add successively earlier 2-mercaptobenzothiazole (1.67g, 10mmol), to amino iodobenzene (2.63g, 12mmol), Catalysts Cu I(0.019g, 0.1mmol), Na
2CO
3(1.06g, 10mmol) and H
2O(20mL), be heated to 120 ℃ of back flow reaction 24h, reaction finishes, be cooled to room temperature, the reaction solution ethyl acetate extraction, the gained organic phase is through saturated aqueous common salt washing, anhydrous sodium sulfate drying, be spin-dried for, PE:EA=6:1 crosses post and gets 4-(2-[4-morpholinodithio sulfenyl) aniline 1.70g, yield 70.0%.
(Π) a kind of preparation of small molecules cathepsin D inhibitor
(1.29g, 5mmol) with 3, (1.04g 5mmol) is dissolved in CH to 5-two chloro-2 hydroxybenzoic acids with gained 4-among the step Ι (2-[4-morpholinodithio sulfenyl) aniline
2CL
2(20mL); add acylating agent 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride (EDC) (0.96g; 5mmol); be heated to 40 ℃ of back flow reaction 8h; reaction finishes, and revolves desolventizing, and PE:EA=3:1 crosses post and gets required small molecules cathepsin D inhibitor N-[4-(benzothiazole-2-sulfo-) aryl]-3; 5-two chloro-2-hydroxybenzamide 1.79g, yield 80.7%.
Embodiment 6:
(Ι) preparation of 4-(2-[4-morpholinodithio sulfenyl) aniline
In reactor, add successively earlier 2-mercaptobenzothiazole (1.67g, 10mmol), to amino iodobenzene (2.63g, 12mmol), Catalysts Cu I(0.19g, 1mmol), K
2CO
3(1.06g, 10mmol) and H
2O(20mL), be heated to 120 ℃ of back flow reaction 24h, reaction finishes, be cooled to room temperature, the reaction solution ethyl acetate extraction, the gained organic phase is through saturated aqueous common salt washing, anhydrous sodium sulfate drying, be spin-dried for, PE:EA=6:1 crosses post and gets 4-(2-[4-morpholinodithio sulfenyl) aniline 2.07g, yield 85.4%.
(Π) a kind of preparation of small molecules cathepsin D inhibitor
(1.29g, 5mmol) with 3, (1.04g 5mmol) is dissolved in CH to 5-two chloro-2 hydroxybenzoic acids with gained 4-among the step Ι (2-[4-morpholinodithio sulfenyl) aniline
2CL
2(20mL); add acylating agent 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride (EDC) (0.96g; 5mmol); be heated to 40 ℃ of back flow reaction 8h; reaction finishes, and revolves desolventizing, and PE:EA=3:1 crosses post and gets required small molecules cathepsin D inhibitor N-[4-(benzothiazole-2-sulfo-) aryl]-3; 5-two chloro-2-hydroxybenzamide 1.79g, yield 80.7%.
Embodiment 7:
(Ι) preparation of 4-(2-[4-morpholinodithio sulfenyl) aniline
In reactor, add successively earlier 2-mercaptobenzothiazole (1.67g, 10mmol), to amino iodobenzene (2.63g, 12mmol), Catalysts Cu I(0.19g, 1mmol), Na
2CO
3(1.06g, 10mmol) and H
2O(20mL), be heated to 140 ℃ of back flow reaction 24h, reaction finishes, be cooled to room temperature, the reaction solution ethyl acetate extraction, the gained organic phase is through saturated aqueous common salt washing, anhydrous sodium sulfate drying, be spin-dried for, PE:EA=6:1 crosses post and gets 4-(2-[4-morpholinodithio sulfenyl) aniline 2.09g, yield 86.0%.
(Π) a kind of preparation of small molecules cathepsin D inhibitor
(1.29g, 5mmol) with 3, (1.04g 5mmol) is dissolved in CH to 5-two chloro-2 hydroxybenzoic acids with gained 4-among the step Ι (2-[4-morpholinodithio sulfenyl) aniline
2CL
2(20mL); add acylating agent 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride (EDC) (0.96g; 5mmol); be heated to 40 ℃ of back flow reaction 8h; reaction finishes, and revolves desolventizing, and PE:EA=3:1 crosses post and gets required small molecules cathepsin D inhibitor N-[4-(benzothiazole-2-sulfo-) aryl]-3; 5-two chloro-2-hydroxybenzamide 1.79g, yield 80.7%.
Embodiment 8:
(Ι) preparation of 4-(2-[4-morpholinodithio sulfenyl) aniline
In reactor, add successively earlier 2-mercaptobenzothiazole (1.67g, 10mmol), to amino iodobenzene (2.63g, 12mmol), Catalysts Cu I(0.19g, 1mmol), Na
2CO
3(1.06g, 10mmol) and H
2O(20mL), be heated to 100 ℃ of back flow reaction 24h, reaction finishes, be cooled to room temperature, the reaction solution ethyl acetate extraction, the gained organic phase is through saturated aqueous common salt washing, anhydrous sodium sulfate drying, be spin-dried for, PE:EA=6:1 crosses post and gets 4-(2-[4-morpholinodithio sulfenyl) aniline 1.82g, yield 75.0%.
(Π) a kind of preparation of small molecules cathepsin D inhibitor
(1.29g, 5mmol) with 3, (1.04g 5mmol) is dissolved in CH to 5-two chloro-2 hydroxybenzoic acids with gained 4-among the step Ι (2-[4-morpholinodithio sulfenyl) aniline
2CL
2(20mL); add acylating agent 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride (EDC) (0.96g; 5mmol); be heated to 40 ℃ of back flow reaction 8h; reaction finishes, and revolves desolventizing, and PE:EA=3:1 crosses post and gets required small molecules cathepsin D inhibitor N-[4-(benzothiazole-2-sulfo-) aryl]-3; 5-two chloro-2-hydroxybenzamide 1.79g, yield 80.7%.
Embodiment 9:
(Ι) preparation of 4-(2-[4-morpholinodithio sulfenyl) aniline
In reactor, add successively earlier 2-mercaptobenzothiazole (1.67g, 10mmol), to amino iodobenzene (2.63g, 12mmol), Catalysts Cu I(0.19g, 1mmol), Na
2CO
3(1.06g, 10mmol) and H
2O(20mL), be heated to 120 ℃ of back flow reaction 24h, reaction finishes, be cooled to room temperature, the reaction solution ethyl acetate extraction, the gained organic phase is through saturated aqueous common salt washing, anhydrous sodium sulfate drying, be spin-dried for, PE:EA=6:1 crosses post and gets 4-(2-[4-morpholinodithio sulfenyl) aniline 2.09g, yield 86.0%.
(Π) a kind of preparation of small molecules cathepsin D inhibitor
(1.29g, 5mmol) with 3, (1.04g 5mmol) is dissolved in CH to 5-two chloro-2 hydroxybenzoic acids with gained 4-among the step Ι (2-[4-morpholinodithio sulfenyl) aniline
2CL
2(20mL); add acylating agent dicyclohexylcarbodiimide (DCC) (1.03g; 5mmol); be heated to 40 ℃ of back flow reaction 8h; reaction finishes, and revolves desolventizing, and PE:EA=3:1 crosses post and gets required small molecules cathepsin D inhibitor N-[4-(benzothiazole-2-sulfo-) aryl]-3; 5-two chloro-2-hydroxybenzamide 1.76g, yield 79.1%.
Embodiment 10:
(Ι) preparation of 4-(2-[4-morpholinodithio sulfenyl) aniline
In reactor, add successively earlier 2-mercaptobenzothiazole (1.67g, 10mmol), to amino iodobenzene (2.63g, 12mmol), Catalysts Cu I(0.19g, 1mmol), Na
2CO
3(1.06g, 10mmol) and H
2O(20mL), be heated to 120 ℃ of back flow reaction 24h, reaction finishes, be cooled to room temperature, the reaction solution ethyl acetate extraction, the gained organic phase is through saturated aqueous common salt washing, anhydrous sodium sulfate drying, be spin-dried for, PE:EA=6:1 crosses post and gets 4-(2-[4-morpholinodithio sulfenyl) aniline 2.09g, yield 86.0%.
(Π) a kind of preparation of small molecules cathepsin D inhibitor
(1.29g, 5mmol) with 3, (1.04g 5mmol) is dissolved in CH to 5-two chloro-2 hydroxybenzoic acids with gained 4-among the step Ι (2-[4-morpholinodithio sulfenyl) aniline
2CL
2(20mL); add acylating agent 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride (EDC) (0.96g; 5mmol); be heated to 20 ℃ of back flow reaction 8h; reaction finishes, and revolves desolventizing, and PE:EA=3:1 crosses post and gets required small molecules cathepsin D inhibitor N-[4-(benzothiazole-2-sulfo-) aryl]-3; 5-two chloro-2-hydroxybenzamide 1.24g, yield 56.1%.
Embodiment 11:
(Ι) preparation of 4-(2-[4-morpholinodithio sulfenyl) aniline
In reactor, add successively earlier 2-mercaptobenzothiazole (1.67g, 10mmol), to amino iodobenzene (2.63g, 12mmol), Catalysts Cu I(0.19g, 1mmol), Na
2CO
3(1.06g, 10mmol) and H
2O(20mL), be heated to 120 ℃ of back flow reaction 4h, reaction finishes, be cooled to room temperature, the reaction solution ethyl acetate extraction, the gained organic phase is through saturated aqueous common salt washing, anhydrous sodium sulfate drying, be spin-dried for, PE:EA=6:1 crosses post and gets 4-(2-[4-morpholinodithio sulfenyl) aniline 1.36g, yield 56.0%.
(Π) a kind of preparation of small molecules cathepsin D inhibitor
(1.29g, 5mmol) with 3, (1.04g 5mmol) is dissolved in CH to 5-two chloro-2 hydroxybenzoic acids with gained 4-among the step Ι (2-[4-morpholinodithio sulfenyl) aniline
2CL
2(20mL); add acylating agent 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride (EDC) (0.96g; 5mmol); be heated to 40 ℃ of back flow reaction 8h; reaction finishes, and revolves desolventizing, and PE:EA=3:1 crosses post and gets required small molecules cathepsin D inhibitor N-[4-(benzothiazole-2-sulfo-) aryl]-3; 5-two chloro-2-hydroxybenzamide 1.79g, yield 80.7%.
Embodiment 12:
(Ι) preparation of 4-(2-[4-morpholinodithio sulfenyl) aniline
In reactor, add successively earlier 2-mercaptobenzothiazole (1.67g, 10mmol), to amino iodobenzene (2.63g, 12mmol), Catalysts Cu I(0.19g, 1mmol), Na
2CO
3(1.06g, 10mmol) and H
2O(20mL), be heated to 120 ℃ of back flow reaction 36h, reaction finishes, be cooled to room temperature, the reaction solution ethyl acetate extraction, the gained organic phase is through saturated aqueous common salt washing, anhydrous sodium sulfate drying, be spin-dried for, PE:EA=6:1 crosses post and gets 4-(2-[4-morpholinodithio sulfenyl) aniline 2.14g, yield 88.0%.
(Π) a kind of preparation of small molecules cathepsin D inhibitor
(1.29g, 5mmol) with 3, (1.04g 5mmol) is dissolved in CH to 5-two chloro-2 hydroxybenzoic acids with gained 4-among the step Ι (2-[4-morpholinodithio sulfenyl) aniline
2CL
2(20mL); add acylating agent 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride (EDC) (0.96g; 5mmol); be heated to 40 ℃ of back flow reaction 8h; reaction finishes, and revolves desolventizing, and PE:EA=3:1 crosses post and gets required small molecules cathepsin D inhibitor N-[4-(benzothiazole-2-sulfo-) aryl]-3; 5-two chloro-2-hydroxybenzamide 1.79g, yield 80.7%.
Embodiment 13:
(Ι) preparation of 4-(2-[4-morpholinodithio sulfenyl) aniline
In reactor, add successively earlier 2-mercaptobenzothiazole (1.67g, 10mmol), to amino iodobenzene (2.63g, 12mmol), Catalysts Cu I(0.19g, 1mmol), Na
2CO
3(1.06g, 10mmol) and H
2O(20mL), be heated to 120 ℃ of back flow reaction 24h, reaction finishes, be cooled to room temperature, the reaction solution ethyl acetate extraction, the gained organic phase is through saturated aqueous common salt washing, anhydrous sodium sulfate drying, be spin-dried for, PE:EA=6:1 crosses post and gets 4-(2-[4-morpholinodithio sulfenyl) aniline 2.09g, yield 86.0%.
(Π) a kind of preparation of small molecules cathepsin D inhibitor
(1.29g, 5mmol) with 3, (1.04g 5mmol) is dissolved in CH to 5-two chloro-2 hydroxybenzoic acids with gained 4-among the step Ι (2-[4-morpholinodithio sulfenyl) aniline
2CL
2(20mL); add acylating agent 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride (EDC) (0.96g; 5mmol); be heated to 40 ℃ of back flow reaction 4h; reaction finishes, and revolves desolventizing, and PE:EA=3:1 crosses post and gets required small molecules cathepsin D inhibitor N-[4-(benzothiazole-2-sulfo-) aryl]-3; 5-two chloro-2-hydroxybenzamide 1.33g, yield 60%.
Embodiment 14:
(Ι) preparation of 4-(2-[4-morpholinodithio sulfenyl) aniline
In reactor, add successively earlier 2-mercaptobenzothiazole (1.67g, 10mmol), to amino iodobenzene (2.63g, 12mmol), Catalysts Cu I(0.19g, 1mmol), Na
2CO
3(1.06g, 10mmol) and H
2O(20mL), be heated to 120 ℃ of back flow reaction 24h, reaction finishes, be cooled to room temperature, the reaction solution ethyl acetate extraction, the gained organic phase is through saturated aqueous common salt washing, anhydrous sodium sulfate drying, be spin-dried for, PE:EA=6:1 crosses post and gets 4-(2-[4-morpholinodithio sulfenyl) aniline 2.09g, yield 86.0%.
(Π) a kind of preparation of small molecules cathepsin D inhibitor
(1.29g, 5mmol) with 3, (1.04g 5mmol) is dissolved in CH to 5-two chloro-2 hydroxybenzoic acids with gained 4-among the step Ι (2-[4-morpholinodithio sulfenyl) aniline
2CL
2(20mL); add acylating agent 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride (EDC) (0.96g; 5mmol); be heated to 40 ℃ of back flow reaction 48h; reaction finishes, and revolves desolventizing, and PE:EA=3:1 crosses post and gets required small molecules cathepsin D inhibitor N-[4-(benzothiazole-2-sulfo-) aryl]-3; 5-two chloro-2-hydroxybenzamide 1.95g, yield 87.9%.
Embodiment 15:
(Ι) preparation of 4-(2-[4-morpholinodithio sulfenyl) aniline
In reactor, add successively earlier 2-mercaptobenzothiazole (1.67g, 10mmol), to amino iodobenzene (2.63g, 12mmol), Catalysts Cu SO
45H
2O(0.25g, 1mmol), Na
2CO
3(1.06g, 10mmol) and H
2O(20mL), be heated to 120 ℃ of back flow reaction 24h, reaction finishes, be cooled to room temperature, the reaction solution ethyl acetate extraction, the gained organic phase is through saturated aqueous common salt washing, anhydrous sodium sulfate drying, be spin-dried for, PE:EA=6:1 crosses post and gets 4-(2-[4-morpholinodithio sulfenyl) aniline 2.07g, yield 85.2%.
(Π) a kind of preparation of small molecules cathepsin D inhibitor
(1.29g, 5mmol) with 3, (1.04g 5mmol) is dissolved in CH to 5-two chloro-2 hydroxybenzoic acids with gained 4-among the step Ι (2-[4-morpholinodithio sulfenyl) aniline
2CL
2(20mL); add acylating agent 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride (EDC) (0.96g; 5mmol); be heated to 40 ℃ of back flow reaction 8h; reaction finishes, and revolves desolventizing, and PE:EA=3:1 crosses post and gets required small molecules cathepsin D inhibitor N-[4-(benzothiazole-2-sulfo-) aryl]-3; 5-two chloro-2-hydroxybenzamide 1.79g, yield 80.7%.
Embodiment 16:
(Ι) preparation of 4-(2-[4-morpholinodithio sulfenyl) aniline
In reactor, add successively earlier 2-mercaptobenzothiazole (1.67g, 10mmol), to amino iodobenzene (2.19g, 10mmol), Catalysts Cu I(0.19g, 1mmol), Na
2CO
3(1.06g, 10mmol) and H
2O(20mL), be heated to 120 ℃ of back flow reaction 24h, reaction finishes, be cooled to room temperature, the reaction solution ethyl acetate extraction, the gained organic phase is through saturated aqueous common salt washing, anhydrous sodium sulfate drying, be spin-dried for, PE:EA=6:1 crosses post and gets 4-(2-[4-morpholinodithio sulfenyl) aniline 2.04g, yield 84.0%.
(Π) a kind of preparation of small molecules cathepsin D inhibitor
(1.29g, 5mmol) with 3, (1.04g 5mmol) is dissolved in CH to 5-two chloro-2 hydroxybenzoic acids with gained 4-among the step Ι (2-[4-morpholinodithio sulfenyl) aniline
2CL
2(20mL); add acylating agent 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride (EDC) (0.96g; 5mmol); be heated to 40 ℃ of back flow reaction 8h; reaction finishes, and revolves desolventizing, and PE:EA=3:1 crosses post and gets required small molecules cathepsin D inhibitor N-[4-(benzothiazole-2-sulfo-) aryl]-3; 5-two chloro-2-hydroxybenzamide 1.79g, yield 80.7%.
Embodiment 17:
(Ι) preparation of 4-(2-[4-morpholinodithio sulfenyl) aniline
In reactor, add successively earlier 2-mercaptobenzothiazole (1.67g, 10mmol), to amino iodobenzene (6.57g, 30mmol), Catalysts Cu I(0.19g, 1mmol), Na
2CO
3(1.06g, 10mmol) and H
2O (20mL) is heated to 120 ℃ of back flow reaction 24h, and reaction finishes, be cooled to room temperature, the reaction solution ethyl acetate extraction, the gained organic phase is through saturated aqueous common salt washing, anhydrous sodium sulfate drying, be spin-dried for, PE:EA=6:1 crosses post and gets 4-(2-[4-morpholinodithio sulfenyl) aniline 2.33g, yield 96.0%.
(Π) a kind of preparation of small molecules cathepsin D inhibitor
(1.29g, 5mmol) with 3, (1.04g 5mmol) is dissolved in CH to 5-two chloro-2 hydroxybenzoic acids with gained 4-among the step Ι (2-[4-morpholinodithio sulfenyl) aniline
2CL
2(20mL); add acylating agent 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride (EDC) (0.96g; 5mmol); be heated to 40 ℃ of back flow reaction 8h; reaction finishes, and revolves desolventizing, and PE:EA=3:1 crosses post and gets required small molecules cathepsin D inhibitor N-[4-(benzothiazole-2-sulfo-) aryl]-3; 5-two chloro-2-hydroxybenzamide 1.79g, yield 80.7%.
Embodiment 18:
(Ι) preparation of 4-(2-[4-morpholinodithio sulfenyl) aniline
In reactor, add successively earlier 2-mercaptobenzothiazole (1.67g, 10mmol), to amino iodobenzene (2.63g, 12mmol), Catalysts Cu I(0.19g, 1mmol), Na
2CO
3(1.06g, 10mmol) and H
2O(20mL), be heated to 120 ℃ of back flow reaction 24h, reaction finishes, be cooled to room temperature, the reaction solution ethyl acetate extraction, the gained organic phase is through saturated aqueous common salt washing, anhydrous sodium sulfate drying, be spin-dried for, PE:EA=6:1 crosses post and gets 4-(2-[4-morpholinodithio sulfenyl) aniline 2.09g, yield 86.0%.
(Π) a kind of preparation of small molecules cathepsin D inhibitor
(2.58g, 10mmol) with 3, (1.04g 5mmol) is dissolved in CH to 5-two chloro-2 hydroxybenzoic acids with gained 4-among the step Ι (2-[4-morpholinodithio sulfenyl) aniline
2CL
2(20mL); add acylating agent 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride (EDC) (0.96g; 5mmol); be heated to 40 ℃ of back flow reaction 8h; reaction finishes, and revolves desolventizing, and PE:EA=3:1 crosses post and gets required small molecules cathepsin D inhibitor N-[4-(benzothiazole-2-sulfo-) aryl]-3; 5-two chloro-2-hydroxybenzamide 1.82g, yield 81%.
Embodiment 19:
(Ι) preparation of 4-(2-[4-morpholinodithio sulfenyl) aniline
In reactor, add successively earlier 2-mercaptobenzothiazole (1.67g, 10mmol), to amino iodobenzene (2.63g, 12mmol), Catalysts Cu I(0.19g, 1mmol), Na
2CO
3(1.06g, 10mmol) and H
2O(20mL), be heated to 120 ℃ of back flow reaction 24h, reaction finishes, be cooled to room temperature, the reaction solution ethyl acetate extraction, the gained organic phase is through saturated aqueous common salt washing, anhydrous sodium sulfate drying, be spin-dried for, PE:EA=6:1 crosses post and gets 4-(2-[4-morpholinodithio sulfenyl) aniline 2.09g, yield 86.0%.
(Π) a kind of preparation of small molecules cathepsin D inhibitor
(1.29g, 5mmol) with 3, (1.04g 5mmol) is dissolved in CH to 5-two chloro-2 hydroxybenzoic acids with gained 4-among the step Ι (2-[4-morpholinodithio sulfenyl) aniline
2CL
2(20mL); add acylating agent 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride (EDC) (1.92g; 10mmol); be heated to 40 ℃ of back flow reaction 8h; reaction finishes, and revolves desolventizing, and PE:EA=3:1 crosses post and gets required small molecules cathepsin D inhibitor N-[4-(benzothiazole-2-sulfo-) aryl]-3; 5-two chloro-2-hydroxybenzamide 1.84g, yield 83%.
Embodiment 20:
(Ι) preparation of 4-(2-[4-morpholinodithio sulfenyl) aniline
In reactor, add successively earlier 2-mercaptobenzothiazole (1.67g, 10mmol), to amino iodobenzene (2.63g, 12mmol), Catalysts Cu I(0.19g, 1mmol), Na
2CO
3(5.30g, 50mmol) and H
2O(20mL), be heated to 120 ℃ of back flow reaction 24h, reaction finishes, be cooled to room temperature, the reaction solution ethyl acetate extraction, the gained organic phase is through saturated aqueous common salt washing, anhydrous sodium sulfate drying, be spin-dried for, PE:EA=6:1 crosses post and gets 4-(2-[4-morpholinodithio sulfenyl) aniline 2.14g, yield 88.1%.
(Π) a kind of preparation of small molecules cathepsin D inhibitor
(1.29g, 5mmol) with 3, (1.04g 5mmol) is dissolved in CH to 5-two chloro-2 hydroxybenzoic acids with gained 4-among the step Ι (2-[4-morpholinodithio sulfenyl) aniline
2CL
2(20mL); add acylating agent 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride (EDC) (0.96g; 5mmol); be heated to 40 ℃ of back flow reaction 8h; reaction finishes, and revolves desolventizing, and PE:EA=3:1 crosses post and gets required small molecules cathepsin D inhibitor N-[4-(benzothiazole-2-sulfo-) aryl]-3; 5-two chloro-2-hydroxybenzamide 1.79g, yield 80.7%.
Embodiment 21:
(Ι) preparation of 4-(2-[4-morpholinodithio sulfenyl) aniline
In reactor, add successively earlier 2-mercaptobenzothiazole (1.67g, 10mmol), to amino iodobenzene (2.63g, 12mmol), Catalysts Cu I(0.57g, 3mmol), Na
2CO
3(1.06g, 10mmol) and H
2O(20mL), be heated to 120 ℃ of back flow reaction 24h, reaction finishes, be cooled to room temperature, the reaction solution ethyl acetate extraction, the gained organic phase is through saturated aqueous common salt washing, anhydrous sodium sulfate drying, be spin-dried for, PE:EA=6:1 crosses post and gets 4-(2-[4-morpholinodithio sulfenyl) aniline 2.19g, yield 91.0%.
(Π) a kind of preparation of small molecules cathepsin D inhibitor
(1.29g, 5mmol) with 3, (1.04g 5mmol) is dissolved in CH to 5-two chloro-2 hydroxybenzoic acids with gained 4-among the step Ι (2-[4-morpholinodithio sulfenyl) aniline
2CL
2(20mL); add acylating agent 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride (EDC) (0.96g; 5mmol); be heated to 40 ℃ of back flow reaction 8h; reaction finishes, and revolves desolventizing, and PE:EA=3:1 crosses post and gets required small molecules cathepsin D inhibitor N-[4-(benzothiazole-2-sulfo-) aryl]-3; 5-two chloro-2-hydroxybenzamide 1.79g, yield 80.7%.
Claims (5)
1. the preparation method of small molecule cathepsin D inhibitor, its concrete steps are:
(Ι) preparation of 4-(2-[4-morpholinodithio sulfenyl) aniline and derivative thereof
In reactor, add earlier 2-mercaptobenzothiazole or its derivative successively, to amino iodobenzene, catalyzer, alkali and solvent, heating reflux reaction, reaction solution are through extraction, drying is crossed post and is got 4-(2-[4-morpholinodithio sulfenyl) aniline and corresponding derivative thereof.
(Π) preparation of small molecules cathepsin D inhibitor
Gained 4-(2-[4-morpholinodithio sulfenyl) aniline in the step (Ι) or its derivative are dissolved in the organic solvent with 3,5-, two chloro-2 hydroxybenzoic acids, the adding acylating agent, reflux, reaction finishes, and aftertreatment is crossed post and is got small molecules cathepsin D inhibitor.
2. preparation method according to claim 1 is characterized in that the 2-mercaptobenzothiazole derivative in the step (Ι) is 2-sulfydryl-6-chloro benzothiazole, 2-sulfydryl-6-methoxyl group benzo thiazole, 2-sulfydryl-5-trifluoromethoxy benzo thiazole, 2-sulfydryl-5-methoxyl group benzo thiazole or 2-sulfydryl-5-ethoxyl benzo thiazole; Described catalyzer is CuI, Cu
2O, CuBr, CuCl, CuO, CuCl
22H
2O, CuSO
45H
2O or Cu; Described alkali is K
2CO
3, K
3PO
4, Na
2CO
3, KOH, NaOH or KOtBu; Acylating agent described in the step (Π) is a kind of in 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride or the dicyclohexylcarbodiimide.
3. preparation method according to claim 1 is characterized in that the solvent described in the step (Ι) is water; Organic solvent described in the step (Π) is methylene dichloride.
4. preparation method according to claim 1 is characterized in that the temperature of reaction described in the step (Ι) is 100-140 ℃, and the reaction times is 4-36h; Temperature of reaction described in the step (Π) is 20-40 ℃, and the reaction times is 4-48h.
5. preparation method according to claim 1, the mol ratio that it is characterized in that the catalyzer described in the step (Ι) and 2-mercaptobenzothiazole or its derivative is 0.01-0.3:1, is 1-3:1 to the mol ratio of amino iodobenzene and 2-mercaptobenzothiazole or its derivative; The mol ratio of alkali and 2-mercaptobenzothiazole or its derivative is 1-5:1; The mol ratio of the acylating agent described in the step (Π) and 3,5-, two chloro-2 hydroxybenzoic acids is 1-2:1, and the mol ratio of 4-(2-[4-morpholinodithio sulfenyl) aniline and corresponding derivative thereof and 3,5-, two chloro-2 hydroxybenzoic acids is 1-2:1.
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CN103923018A (en) * | 2014-04-29 | 2014-07-16 | 山西大学 | Method for preparing heteroatom-containing aromatic sulfide |
CN105001300A (en) * | 2014-04-17 | 2015-10-28 | 复旦大学 | Cathepsin D inhibitor, preparation method, pharmaceutical composition and applications thereof |
CN112635827A (en) * | 2020-12-04 | 2021-04-09 | 上海应用技术大学 | Electrolyte additive, electrolyte containing additive and lithium ion battery |
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Cited By (4)
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CN105001300A (en) * | 2014-04-17 | 2015-10-28 | 复旦大学 | Cathepsin D inhibitor, preparation method, pharmaceutical composition and applications thereof |
CN103923018A (en) * | 2014-04-29 | 2014-07-16 | 山西大学 | Method for preparing heteroatom-containing aromatic sulfide |
CN112635827A (en) * | 2020-12-04 | 2021-04-09 | 上海应用技术大学 | Electrolyte additive, electrolyte containing additive and lithium ion battery |
CN112635827B (en) * | 2020-12-04 | 2022-07-19 | 上海应用技术大学 | Electrolyte additive, electrolyte containing additive and lithium ion battery |
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